Mechanisms by Which Chronic Ethanol Feeding Limits the Ability of Dendritic Cells to Stimulate T-Cell Proliferation

Fan, Jie; Edsen-Moore, Michelle; Turner, Lucas; Cook, Robert T.; Legge, Kevin L.; Waldschmidt, Thomas J.; Schlueter, Annette J.

doi:10.1111/j.1530-0277.2010.01321.x

Cited by 30 publications

(26 citation statements)

References 97 publications

(116 reference statements)

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“…However, it is likely that other defects within mice chronically consuming EtOH (such as IL-2 expression by CD4 T cells and defects within APCs) contribute to inappropriate and/or insufficient priming of IAV-specific CD8 T cells within dLN. Changes in antigen presenting cell populations have been well documented to occur during EtOH exposure (Fan et al, 2011, Ness et al, 2008, Parlet and Schlueter, 2013, Edsen-Moore et al, 2008, Legge and Waldschmidt, 2014, Gurung et al, 2009, Buttari et al, 2008, Happel and Nelson, 2005, Joshi and Guidot, 2007, Szabo and Mandrekar, 2009, Zhang et al, 2002, Eken et al, 2011, Joshi et al, 2005, Lau et al, 2007, Mehta and Guidot, 2012, Rendon et al, 2012, Siggins et al, 2009, Szabo and Mandrekar, 2008). While dendritic cell functionality during IAV challenge of mice chronically consuming EtOH has not been completely investigated, the migration of dermal DCs, cutaneous DCs and Langerhans cells is delayed following FITC sensitization (Ness et al, 2008, Parlet and Schlueter, 2013).…”

Section: Discussionmentioning

confidence: 99%

Chronic Ethanol Exposure Selectively Inhibits the Influenza‐Specific CD8 T Cell Response During Influenza A Virus Infection

Hemann

McGill

Legge

2014

Alcoholism Clin & Exp Res

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Background It is well established that chronic ethanol (EtOH) consumption is associated with increased incidence and disease severity of respiratory infections. Our recent work demonstrates this increase in disease severity to influenza virus (IAV) infections is due, in part, to a failure to mount a robust IAV-specific CD8 T cell response along with a specific impairment in the ability of these T cells to produce IFNγ. However, the full extent of the lesion in the effector CD8 T cell compartment during chronic EtOH consumption remains unknown. Methods Utilizing the Meadows-Cook murine model of chronic alcohol consumption, mice received EtOH in their drinking water for 8 or 12 weeks. Mice were challenged intranasally with IAV and the activation and effector functions of IAV specific CD8 T cells were determined in both the lung-draining lymph nodes and lungs. Results Our results confirm the defect in interferon γ (IFNγ) production, however, the ability of IAV-specific T cells to produce tumor necrosis factor α (TNFα) and interleukin-2 (IL-2) in EtOH-consuming mice remains unaltered while interferon γ (IFNγ) production. In contrast, EtOH consumption significantly reduces the ability of CD8 T cells to degranulate and kill IAV-specific targets. Finally, our findings suggest the lesion begins during the initial activation of CD8 T cells, as we observe early defects in proliferation in the lung-draining lymph nodes (dLN) of IAV-infected, EtOH-consuming mice. Conclusions These findings highlight the previously unrecognized depth of the lesion in the IAV-specific CD8 T cell response during chronic EtOH consumption. Given the important role CD8 T cell immunity plays in control of IAV, these findings may aid in the development of vaccination and/or therapeutic strategies to reverse these defects in the CD8 T cell response and reduce serious disease outcomes associated with IAV infections in alcoholics.

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Section: Discussionmentioning

confidence: 99%

Chronic Ethanol Exposure Selectively Inhibits the Influenza‐Specific CD8 T Cell Response During Influenza A Virus Infection

Hemann

McGill

Legge

2014

Alcoholism Clin & Exp Res

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“…3). Given that peripheral DCs are involved in Treg induction/expansion pathways and chronic EtOH feeding causes defects in DC numbers and function, EtOH-induced alterations in DC/T cell interactions in the skin or skin-draining LNs may contribute to dermal Treg loss (Fan et al, 2011; Lau et al, 2009; Ness et al, 2008; Parlet and Schlueter, 2013). Additionally, Tregs are highly motile cells that routinely traffic into and out of the skin, raising the possibility that altered migration patterns underlie the EtOH-induced reduction in dermal Tregs (Tomura et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Chronic Ethanol Feeding Induces Subset Loss and Hyporesponsiveness in Skin T Cells

Parlet

Waldschmidt

Schlueter

2014

Alcoholism Clin & Exp Res

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Background Chronic alcoholism is associated with increased incidence and severity of cutaneous infection. Skin-resident T cells orchestrate numerous immunological functions that are critically involved in both tissue homeostasis and cutaneous immunity. The impact of chronic ethanol (EtOH) exposure on skin T cells has not previously been examined; given their important role in maintaining the immune barrier function of the skin further study is warranted. Methods Mice were administered EtOH in the drinking water for 12 to 16 weeks. Flow cytometry was used to evaluate impact of EtOH feeding on skin T cell numbers, rates of proliferation, and apoptosis as well as activation marker expression and cytokine production after ex vivo stimulation. Results Chronic EtOH feeding caused a baseline reduction in dendritic epidermal T cell (DETC) numbers that corresponded with reduced expression of the activation marker JAML following phorbol 12-myristate 13-acetate (PMA)/ionomycin stimulation. Chronic EtOH feeding did not alter total numbers of dermal T cells, but specific subset loss was observed in Foxp3+ regulatory T cells (Tregs) as well as CD3hi, Vγ3+ and CD3int, Vγ3− dermal γδ T cells. EtOH-induced dysfunction in the latter population, which represents prototypical interleukin-17 (IL-17)-producing dermal γδT17s, was made evident by diminished IL-17 production following anti-CD3 stimulation. Additionally, the capacity of lymph node γδ T cells to produce IL-17 following anti-CD3 and PMA/ionomycin stimulation was impaired by chronic EtOH feeding. Conclusions Chronic EtOH feeding induced defects in both numbers and function of multiple skin T cell subsets. The decreased density and poor responsiveness of DETCs and γδT17 cells in particular would be expected to compromise immune effector mechanisms necessary to maintain a protective barrier and restrict pathogen invasion. These findings demonstrate the sensitivity of skin T cells to EtOH and provide new mechanisms to help explain the propensity of alcoholics to suffer skin infection.

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“…However, it is likely that other defects within mice chronically consuming EtOH (such as IL-2 expression by CD4 T cells and defects within APCs) contribute to inappropriate and/or insufficient priming of IAV-specific CD8 T cells within dLN. Changes in antigen presenting cell populations have been well documented to occur during EtOH exposure (Fan et al, 2011, Parlet and Schlueter, 2013, Legge and Waldschmidt, 2014, Gurung et al, 2009, Buttari et al, 2008, Happel and Nelson, 2005, Joshi and Guidot, 2007, Szabo and Mandrekar, 2009, Zhang et al, 2002, Eken et al, 2011, Joshi et al, 2005, Lau et al, 2007, Mehta and Guidot, 2012, Rendon et al, 2012, Siggins et al, 2009, Szabo and Mandrekar, 2008. While dendritic cell functionality during IAV challenge of mice chronically consuming EtOH has not been completely investigated, the migration of dermal DCs, cutaneous DCs and Langerhans cells is delayed following FITC sensitization (Ness et al, 2008, Parlet andSchlueter, 2013).…”

Section: Discussionmentioning

confidence: 99%

Chronic ethanol exposure selectively inhibits the influenza-specific CD8 T cell response during influenza A virus infection

Hemann

McGill

Waldschmidt

et al. 2013

Alcohol

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Mechanisms by Which Chronic Ethanol Feeding Limits the Ability of Dendritic Cells to Stimulate T-Cell Proliferation

Cited by 30 publications

References 97 publications

Chronic Ethanol Exposure Selectively Inhibits the Influenza‐Specific CD8 T Cell Response During Influenza A Virus Infection

Chronic Ethanol Exposure Selectively Inhibits the Influenza‐Specific CD8 T Cell Response During Influenza A Virus Infection

Chronic Ethanol Feeding Induces Subset Loss and Hyporesponsiveness in Skin T Cells

Chronic ethanol exposure selectively inhibits the influenza-specific CD8 T cell response during influenza A virus infection

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